Leprosy is a fascinating disease for many reasons. Historical, because, well, it’s leprosy. Genetic, because the bacterium is apparently derived from a single clone that infected humans some 4000 years ago,1 and that has undergone “massive gene decay” in the process of becoming an obligate pathogen:

Thus, since diverging from the last common mycobacterial ancestor, the leprosy bacillus may have lost more than 2,000 genes. 2

Immunological, because as mycobacteria, leprosy and tuberculosis may have an entire branch of the immune system dedicated to their control and destruction. Epidemiological, because leprosy is one of the very few diseases that has the potential for elimination without vaccines. And now let’s add phylogeography and anthropology to the list, with a paper that offers a detailed analysis of leprosy’s migration through humanity. 3

This was done by genetic analysis, tracking through sub-types of leprosy in various areas, both modern and ancient — the latter being “obtained from leprosy graveyards in Croatia, Denmark, Egypt, England, Hungary and Turkey“, and allowing the authors to determine the strains of leprosy that circulated as much as 1500 years ago. Their conclusions (building on and extending earlier work):

The progenitor of leprosy arose in East Africa

New strains then spread into Asia, through two different routes: One northern route, and one southern

The Southern route into Asia was probably the Silk Road: “the trade route between Europe and Asia known as the Silk Road appears likely to have been a means of transport and disease transmission“. They point out that this is the opposite path of the Black Plague, which likely spread from Asia to Europe along the Silk Road.

Another strain of leprosy moved from East Africa westward into the Middle East and Europe

This strain in turn spawned strains that are found in West Africa and countries linked to West Africa by the slave trade. (Compare to the phylogeography of hepatitis C, among other diseases spread by slavery)

Leprosy in North America came from relatively recent European immigrants, rather than coming along with the original Bering Strait peoples.

“Pillars are located on the country of origin of the M. leprae sample … The gray arrows indicate the migration routes of humans, with the estimated time of migration in years shown. The red dots indicate the location of the Silk Road in the first century.” 3 (Click for a larger version)

One interesting conclusion is that the genome decay of M. leprae is much older than humans (occurring over a million years ago, whereas humans are only a few hundred thousand years old), even though the genetic evidence says the present bacteria were clonal just a few thousand years ago. They suggest that

Alternatively, the genome decay could well be ancient, but M. leprae may only recently have become a human pathogen. For instance, it is conceivable that an ancestral form of M. leprae infected an invertebrate host such as an insect, which later acted as a vector for transmitting the bacillus to humans. 3

… in a household setting, simple, readily available products such as 1% bleach, 10% vinegar and 0.01% washing up liquid all make convenient, easy to handle killing agents for influenza virus A/H1N1. These findings can be readily translated into simple public health advice, even in low resource settings. The public do not need to source more sophisticated cleaning products than these.

(My emphasis) Their figures show that these common solutions almost immediately reduced the numbers of virus from between 1 and 100 million at the start, to undetectable levels (less than 200). Hot water, not surprisingly, didn’t work.

They also added that “branded anti-bacterial wipes and anti-viral tissues were encouragingly effective at inactivating the virus“, so if you’d rather buy something expensive, go ahead.

Ladies & Gentlemen, I give you The Fever Districts of the United States, as of 1856 (click for a larger version):

Note the outlining of the Intermittent Fever districts, including Lansing, MI, where I live. Note the intense yellow rim of Yellow Fever. Note the Small Pox Measles Scarlatina Consumption Endemic region along the Eastern seaboard, the large-case TYPHUS, the DYSENTERY, the casual “And many epidemics” tacked on to the main Yellow Fever, the serpentine red band tracing cholera. 1 There’s goitre in the Midwest and Mexico, elephantiasis down in South America, “Dia. & Dys. (severe)” in tiny writing down in the Bahamas, and the Bermudas are “generally healthy: Influenza, Rheumatism, Dysentery, Yellow Fever”. And so much more. (Compare to the map of Malaria in the USA, 1870.)

This amazing map is a mere afterthought, an inset of a map whose awesomeness goes up to 11. The US map to the right2 (again, click for a larger version) is still just a small fraction of the whole, and that’s not even mentioning the jaw-dropping charts and graphs, also inset, showing “Consumption: Proportion of Deaths in the different quarters of the Globe”, “Comparative Value of Life in Different Countries”, “Proportionate Mortality of European Residents in Foreign Countries” and still more and more.

This map is “The geographical distribution of health & disease, in connection chiefly with natural phenomena. (with) Fever districts of United States & W. Indies, on an enlarged scale,” and it’s from:

I’d run across reverent mentions of this map — especially the Fever Districts inset — here and there in old books, and I just stumbled across it in downloadable form. You must go at once to The David Rumsey Collection and pore over it for several hours, at the highest resolution.

Lansing seems to have been just barely cholera-free, at least in 1856.[↩]

A couple of days ago I posted this map of malaria in the USA. It got picked up by Grant Jacobs, who made some interesting and useful comments, and that in turn got picked up by someone who posted it to boingboing.net. Unfortunately, whoever wrote it up for boingboing tried to add some value by offering a couple of points on the history of malaria, both of which were wrong. 1 In particular, he claimed that “It wasn’t until 1908 that a Cuban doctor made the connection with mosquitoes”. To set the record straight:

RECENT researches by Surgeon Major Ronald Ross have shown that the mosquito may be the host of parasites of the type of that which causes human malaria. Ross has distinctly proved that malaria can be acquired by the bite of a mosquito, and the results of his observations have a direct bearing on the propagation of the disease in man. Dr P. Manson describes the investigations in a paper in the British Medical Journal, and sums them up as follows: –The observation tend to the conclusion that the malaria parasite is for the most part a parasite of insects; that it is only an accidental and occasional visitor to man; that not all mosquitos are capable of subserving it; that particular species of malaria parasites demand particular species of mosquitos; that in this circumstance we have at least a partial explanation of the apparent vagaries of the distribution of the varieties of malaria. When the whole story has been completed, as it surely will be at no distant date, in virtue of the new knowledge thus acquired we shall be able to indicate a prophylaxis for malaria of a practical character, and one which may enable the European to live in climates now rendered deadly by this pest.

—Nature, Sept. 1898. p. 523

The earliest probable reference I can find2 is from 1896:
The Goulstonian Lectures on the Life History of the Malaria Germ Outside the Human Body. P. Manson. The British Medical Journal, 1896

Update: I just realized what the boingboing.net poster had in mind with his comment that “It wasn’t until 1908 that a Cuban doctor made the connection with mosquitoes”: He was thinking about yellow fever, a virus rather than a parasite. Here and there about the web it’s suggested that yellow fever was shown to be mosquito-borne, in 1908, by a Cuban doctor, Carlos Finlay. Unfortunately that’s also not correct; it probably was originally a typo somewhere that got spread around.

Finlay (who was, I believe, American, though he worked in Cuba) originally published his observations in 18813 and then in English in 18891886.4 His theory wasn’t immediately accepted, but by 1900 it was confirmed by a medical commission that included the famous Walter Reed.

Also, he didn’t credit me, which is probably for the best, since my pathetic hosting would have undoubtedly crashed[↩]

Intracellular proteins have to be degraded, more or less at the same rate as new proteins are produced (or the cell would eventually burst). On the other hand, you can’t go about degrading proteins willy-nilly. There are vast and complex systems for identifying proteins that should be destroyed, tagging them, and then moving them into a controlled destruction chamber.

The most important of these systems is the ubiquitin-proteasome degradation pathway. Proteins that are destined for destruction are tagged with a chain of ubiquitin molecules.1 There are multiple steps in this pathway, in which ubiquitin is prepared for tagging, target proteins are identified, and ubiquitin is transferred from the activating components to the targeted protein.

Target proteins are destroyed when a chain of ubiquitin molecules (head to tail) are attached to them. An unanswered question has been how this works. Is the ubiquitin chain formed first, and then transferred to the target en bloc? Or are single ubiquitin transferred one at a time, sequentially, first to the target protein and then to the previously-attached ubiquitins? The problem has been that the process goes so fast that it’s been hard to distinguish between the possibilities.

Now, in a gorgeous series of experiments, Pierce et al2 were able to watch ubiquitination happening over fractions of a second:

… we performed our single-encounter reactions on a quench flow apparatus that allowed us to take measurements on a timescale ranging from 10 ms to 30 s2

And the answer looks pretty clear: Ubiquitins are transferred sequentially, not en bloc.

Even at this timescale, though, they weren’t able to catch the very first event — the transfer of the first ubiquitin to the target. That happens, apparently, in less than 10-20 milliseconds. They also draw the conclusion that target tagging is critically dependent on the kinetics of ubiquitin chain elongation (as you’d expect) which are governed by ubiquitin off-rates, and this mode of regulation is probably a billion years old.

Figure 3d: Kinetics of ubiquitin addition and elongation2(Click for a larger version)

Apple’s iWorks ’06 package was interesting, but ended up being too simplified to really compete with MS Office. But iWorks ’09 was a big step forward, and I now use Pages for almost all my word processing, and Numbers for about 75% of my spreadsheets. (I still use Powerpoint for most of my slideshows; I don’t find any compelling reason to use Keynote instead, and Powerpoint does have some distinct advantages.)

“Numbers” looks fairly similar to Excel — they are both spreadsheet programs, so there’s only so many ways of usefully presenting information there — but the editing and so on can be quite different from Excel, which can be frustrating if you’re coming from an Excel background. Rosie Redfield was just complaining about the non-intuitiveness of Numbers. I don’t think it’s non-intuitive, just different from Excel.

So I put together a couple quick screencasts of making a line graph and a scatter plot, in the hope it would give a starting point for people new to Numbers. (Flash movies, 7.8 and 5 MB respectively. No sound, because my kids are still asleep.) I’ve never tried this before, but hopefully they’ll work.